CE17 - Recherche translationnelle en santé

Synchrotron therapy for Epilepsy – STEP

Our preclinical expertise and the recent experience of patient irradiation at the ESRF, as well as the close collaboration with the Grenoble University Hospital should make the First-in-man clinical trial of MRT possible in 2025. To reach this ambitious goal, STEP will determinate the optimal MRT procedures for an efficient seizure suppression in a rat model of mesiotemporal lobe epilepsy (WP1) and will correlate this information with toxicity thresholds determined in normal rats and minipigs (WP2). These data will help to prepare the documentation required by regulatory and safety French agencies and to design an adapted protocol for the first safety clinical trial in epileptic patients (WP3).
The choice to first consider mesiotemporal lobe epilepsy (MTLE) is motivated by several aspects: (i) it is a typical and well described drug-resistant focal epilepsy; (ii) surgical resection of the epileptic zone following craniotomy, is the current gold-standard therapeutic option for this form of epilepsy, is effective in 50 to 80% of cases, but remains risky and has a significant cost for the Health Systems; (iii) the Grenoble University Hospital epilepsy surgery program has accumulated a strong expertise of MTLE patients so that obtaining a significant cohort for the clinical trials should be straightforward; (iv) animal models of MTLE have been well described and members of the consortium already have the expertise to use such models.

Our first results obtained in a predictive model of MTLE in mice show that irradiation of the epileptic focus with microbeams of 50 µm width, spaced 400 µm apart, makes it possible to significantly suppress focal seizures for a period of up to 8 months after irradiation. When the dose applied to the target area is less than 250 Gy, this suppression of seizures is not accompanied by any side effects on the behavior of the animals, and rather improves their learning disorder.

Due to the cessation of activity of the synchrotron biomedical line in July 2023, experiments on healthy animals (rats and minipigs) cannot be carried out. As an alternative, we will examine the effect of irradiations using full beams (control) and minibeams (500 µm) using an X-ray irradiator for rodents, thus reproducing conditions closer to the clinic.

Samalens L, Courivaud C, Adam JF, Barbier EL, Serduc R, Depaulis A. Innovative minimally invasive options to treat drug-resistant epilepsies. Rev Neurol (Paris). 2023 Oct 3:S0035-3787(23)01038-X. doi: 10.1016/j.neurol.2023.05.006. Epub ahead of print. PMID: 37798162.

Submission summary

STEP’s primary objective is to collect all necessary preclinical data on the efficacy and safety of synchrotron-generated microbeams to make possible a First-in-man clinical trial in patients with refractory mesio-temporal lobe epilepsy in the aftermath. STEP represents the transition between 20 years of basic research on Microbeam Radiation Therapy (MRT) and the clinical development of an innovative radiosurgery approach of brain diseases.
During the last twenty years, the extremely high flux of photons generated by 3rd generation synchrotrons, has enabled the development of novel irradiation strategies holding great promises for innovative radiotherapy. In particular, the possibility to split weakly diverging synchrotron-generated X-rays into arrays of 50-µm wide microbeams, separated by 200-800 µm, has allowed the emergence of the MRT. Several pre-clinical studies performed by STEP partners and other groups have shown that MRT offers a particularly safe procedure to transect or lesion specific brain regions without the usual tissular, vascular or behavioral side effects of conventional radiotherapy. The collaboration between engineers, researchers and clinicians of the Biomedical Beamline (ID17) at the European Synchrotron Radiation Facility (ESRF), INSERM, and University Hospital of Grenoble-Alpes has shown the efficacy of MRT in animal models of Epilepsy to suppress seizures and neuronal synchronization over several months, without histological or functional deleterious side effects. Therefore, MRT has the potential to become a disruptive technology for treating diseases where the target is closely surrounded by tissues whose function should be preserved, as in focal epilepsies and several other neurological diseases.
Our preclinical expertise and the recent experience of patient irradiation at the ESRF, as well as the close collaboration with the Grenoble University Hospital should make the First-in-man clinical trial of MRT possible in 2025. To reach this ambitious goal, STEP will determinate the optimal MRT procedures for an efficient seizure suppression in a rat model of mesiotemporal lobe epilepsy (WP1) and will correlate this information with toxicity thresholds determined in normal rats and minipigs (WP2). These data will help to prepare the documentation required by regulatory and safety French agencies and to design an adapted protocol for the first safety clinical trial in epileptic patients (WP3).
The choice to first consider mesiotemporal lobe epilepsy (MTLE) is motivated by several aspects: (i) it is a typical and well described drug-resistant focal epilepsy; (ii) surgical resection of the epileptic zone following craniotomy, is the current gold-standard therapeutic option for this form of epilepsy, is effective in 50 to 80% of cases, but remains risky and has a significant cost for the Health Systems; (iii) the Grenoble University Hospital epilepsy surgery program has accumulated a strong expertise of MTLE patients so that obtaining a significant cohort for the clinical trials should be straightforward; (iv) animal models of MTLE have been well described and members of the consortium already have the expertise to use such models.
All members of the consortium have the complementary expertise to conduct this project and have been working together for more than 5 years. The strengths of STEP relies on high-level and robust preclinical studies, which pave the way for a smooth translation towards Phase I clinical trials. We believe that STEP will provide a disruptive therapeutic approach, potentially applicable outside the epilepsy field.

Project coordination

Antoine Depaulis (GRENOBLE INSTITUT DES NEUROSCIENCES (GIN))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

NUMECAN-INRAE Nutrition, métabolismes et cancer
GIN GRENOBLE INSTITUT DES NEUROSCIENCES (GIN)
CHUGA/CIC 1406 Centre Hospitalio-Universitaire Grenoble Alpes
STROBE Rayonnement SynchoTROn pour la Recherche BiomédicalE

Help of the ANR 569,830 euros
Beginning and duration of the scientific project: March 2021 - 48 Months

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